1. Field of the Invention
This invention relates to compounds, to processes of their preparation, to pharmaceutical compositions containing them and to their medical use as agonists at kappa opioid receptors.
2. Reported Developments
Opium and its derivatives are potent analgesics that also have other pharmacological effects, and exert their effects by interacting with high-affinity receptors.
It has been shown by investigators that there are at least three major opioid receptor types in the central nervous system (hereinafter CNS) and in the periphery. These receptors, known as mu (xcexc), delta (xcex4) and kappa (xcexa), have distinct pharmacological profiles, anatomical distributions and functions. [See, for example: Wood, P. L., Neuropharmacology, 21, 487-497, 1982; Simon, E. J., Med. Res. Rev., 11, 357-374, 1991; Lutz et al, J. Recept. Res. 12, 267-286; and Mansour et al, Opioid I, ed. Herz,. A. (Springer, Berlin) pp. 79-106, 1993.] The xcex4 receptors are abundant in CNS and mediate analgesia, gastrointestinal motility and various hormonal functions. The xcexc receptors bind morphine-like drugs and mediate the opiate phenomena associated with morphine, including analgesia, opiate dependence, cardiovascular and respiratory functions, and several neuroendocrine effects.
The xcexa receptors have a wide distribution in CNS and mediate a spectrum of functions including the modulation of drinking, water balance, food intake, gut motility, temperature control and various endocrine functions. They also produce analgesia. [See, for example: Leander et al, J. Pharmacol. Exp. Ther. 234, 463-469, 1985; Morley et al, Peptides 4, 797-800, 1983; Manzanares et al, Neuroendocrinology 52, 200-205, 1990; and Iyengar et al, J. Pharmacol. Exp. Ther, 238, 429-436, 1986.]
Most clinically used opioid analgesics such as morphine and codeine act as xcexc receptor agonists. These opioids have well-known, undesirable and potentially dangerous dependence forming side effects. Compounds which are xcexa-receptor agonists act as analgesics through interaction with xcexa opioid receptors. The advantage of these agonists over the classical xcexc receptor agonists, such as morphine, lies in their ability to cause analgesia while being devoid of morphine-like behavioral effects and addiction liability.
A large number of classes of compounds which act as agonists at xcexa opioid receptors have been described in the art including the following illustrative classes of compounds.
U.S. Pat. No. 4,065,573 discloses 4-amino-4-phenylcyclohexane ketal compounds having analgesic activity.
U.S. Pat. No. 4,212,878 discloses phenylacetamide derivatives having analgesic properties and reduced physical dependence liability properties, relative to morphine and methadone.
U.S. Pat. No. 4,145,435 discloses N-(2-amino-cycloaliphatic)-phenylacetamide compounds having analgesic activity and narcotic antagonist activity.
U.S. Pat. No. 4,098,904 discloses N-(2-amino-cycloaliphatic)-benzoamides and naphthamides useful for relieving pain.
U.S. Pat. No. 4,359,476 discloses substituted cycloalkane-amides useful as analgesic and having low abuse liability.
U.S. Pat. No. 4,438,130 discloses 1-oxa-, aza- and thia-spirocyclic compounds having analgesic activity, low physical dependence and abuse liability properties and little dysphoric inducing properties.
U.S. Pat. No. 4,663,343 discloses substituted naphthalenyloxy-1,2-diaminocyclohexyl amides as analgesics.
U.S. Pat. No. 4,906,655 discloses 1,2-cyclohexylaminoaryl amides having high kappa-opioid affinity, selectivity and potency and useful as analgesics, diuretics, anti-inflammatory and psychotherapeutic agents.
Compounds having kappa opioid agonist activity, compositions containing them and method of using them as analgesics are provided.
In its compound aspect, the present invention provides a compound of the formulae I, II, IIA, III, IIIA, IV and IVA, or a pharmaceutically acceptable salt thereof
The compounds of formula (I) have the following structure: 
wherein
nxe2x88x921-3, where n=1 is preferred
R1 and R2 are independently xe2x95x90CH3; xe2x80x94(CH2)m, where m=4-8, m=4 is most preferred; xe2x80x94CH2CH(OH)(CH2)2xe2x80x94; CH2CH(F)(CH2)2xe2x80x94; xe2x80x94(CH2)2O(CH2)2xe2x80x94; or xe2x80x94(CH2)2CHxe2x95x90CHCH2xe2x80x94;
Ar=unsubstituted or mono- or di-substituted phenyl wherein said substituents are selected from the group consisting of halogen, OCH3, SO2CH3, CF3, amino, alkyl, and 3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;
Z is
xe2x80x94P(O)(OBn)2; xe2x80x94P(O)(OH)2; xe2x80x94(CH2)pC(O)NHOH; xe2x80x94(CH2)pCO2H; xe2x80x94SO2CH3; xe2x80x94SO2NH2; xe2x80x94CO(CH2)pCH(NH2)(CO2H); xe2x80x94COCH(NH2)(CH2)pCO2H; xe2x80x94CO2CH3; xe2x80x94CONH2; xe2x80x94(CH2)pO(CH2)pCO2H; xe2x80x94(CH2)pO(CH2)pCONHOH; xe2x80x94(CH2)pNHSO2CH3; xe2x80x94(CH2)pNCH(S)NHCH(CO2H)(CH2)pCO2H; xe2x80x94(CH2)pSO3H; or 
or Z is 
xe2x80x83wherein
p=0-20;
R3=xe2x80x94H or xe2x80x94Ac;
X2=xe2x80x94CO2H; xe2x80x94NHSO2CH3; NHP(O)(OBn)2, NHP(O)(OH)2,
xe2x80x94OP(O)(OBn)2; or OP(O)(OH)2;
X and Y are independently
xe2x80x94CH2NHSO2CH3, xe2x80x94CH2NHP(O)(OBn)2, xe2x80x94CH2NHP(O)(OH)2, xe2x80x94CH2OP(O)(OBn)2, xe2x80x94CH2OP(O)(OH)2, xe2x80x94(CH2)qO(CH2)qCO2H, xe2x80x94(CH2)qO(CH2)qSO3H, xe2x80x94(CH2)qO(CH2)qCHNHOH, xe2x80x94CH2NHC(S)NHCH(CO2H)(CH2)qCO2H or 
xe2x80x83wherein
r=1-20
R4=xe2x80x94H or xe2x80x94Ac
X3=xe2x80x94CO2H; xe2x80x94NHSO2CH3; xe2x80x94NHP(O)(OBn)2; xe2x80x94NHP(O)(OH)2; xe2x80x94OP(O)(OBn)2; or xe2x80x94OP(O)(OH)2.
The compounds of formula II have the following structure: 
wherein
n=1-3, where n=1 is preferred
R1 and R2 are independently xe2x95x90CH3; xe2x80x94(CH2)m, where m=4-8, m=4 is most preferred; xe2x80x94CH2CH(OH)(CH2)2xe2x80x94; CH2CH(F)(CH2)2xe2x80x94; xe2x80x94(CH2)2O(CH2)2xe2x80x94; or xe2x80x94(CH2)2CHxe2x95x90CHCH2xe2x80x94;
Ar=unsubstituted or mono- or di-substituted phenyl wherein said substituents are selected from the group consisting of halogen, OCH3, SO2CH3, CF3, amino, alkyl, and 3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;
X4 and X5 are independently
xe2x80x94OP(O)(OBn)2; xe2x80x94OP(O)(OH); xe2x80x94CO2H; xe2x80x94SO3H; xe2x80x94SO3H; xe2x80x94O(CH2)nCO2H; xe2x80x94NHSO2CH3; xe2x80x94CONH(CH2)sCO2H; or xe2x80x94SO2NH(CH2)sCO2H; wherein
s=1-5
or X4 and X5 are independently 
xe2x80x83wherein
t=1-20
R5=xe2x80x94H or xe2x80x94Ac
X6xe2x80x94CO2H; xe2x80x94NHSO2CH3; xe2x80x94NHP(O)(OBn)2; xe2x80x94NHP(O)(OH)2; xe2x80x94OP(O)(OBn)2; or xe2x80x94OP(O)(OH)2.
The compounds of formula IIA have the following structure: 
wherein
n=1-3, where n=1 is preferred
R1 and R2 are independently xe2x95x90CH3; xe2x80x94(CH2)m, where m=4-8, m=4 is most preferred; xe2x80x94CH2CH(OR)(CH2)2xe2x80x94 wherein R is H, alkyl, acyl or aroyl; CH2CH(F)(CH2)2xe2x80x94; xe2x80x94(CH2)2O(CH2)2xe2x80x94; or xe2x80x94(CH2)2CHxe2x95x90CHCH2xe2x80x94;
Ar=mono- or di-substituted phenyl; wherein said substituents are selected from the group consisting of halogen, OCH3, OH, SO2CH3, CF3, NH2, alkyl, CN, unsubstituted and substituted sulfamoyl groups;
Ar may also be substituted with
xe2x80x94NH(CH2)uCO2Rxe2x80x2; xe2x80x94NH(CH2)u(CHxe2x95x90CH)u(CH2)CO2Rxe2x80x2; xe2x80x94NHCO(CH2)u(CHxe2x95x90CH)u(CH2)uCO2Rxe2x80x2; xe2x80x94NHP(O)(OBn)2; xe2x80x94NHP(O)(ORxe2x80x2)2; xe2x80x94(CH2)uNHSO2CH3; xe2x80x94(CH2)NHC(S)NHCH(CO2Rxe2x80x2)(CH2)CO2Rxe2x80x2; xe2x80x94CONHOH; or xe2x80x94(CH2)uCONHOH;
xe2x80x83wherein
u=0-5;
Rxe2x80x2=H or lower alkyl;
or Ar is 
R6=xe2x80x94H or xe2x80x94Ac
R7=xe2x80x94NH(CH2)vCO2H; xe2x80x94NH(CH2)vCH(NH2)(CO2H); xe2x80x94NHCH(CO2H)(CH2)vNH2; xe2x80x94NH(CH2)vSO3H; xe2x80x94NH(CH2)vPO3H2; xe2x80x94NH(CH2)vNHC(NH)NH2; or xe2x80x94NHCH(CO2H)(CH2H)vCO2H; and
X8=xe2x80x94CO2H; xe2x80x94NHSO2CH3; xe2x80x94NHP(O)(OBn)2; xe2x80x94NHP(O)(OH)2; xe2x80x94OP(0)(OBn)2; or xe2x80x94OP(O)(OH)2;
v=1-20.
X4 and X5 are independently H; halogen; OH; OCH3; CF3; NO2; NH2; amino substituted with acyl, carbamate, alkyl or aryl sulfonates; CORxe2x80x2 where Rxe2x80x2 is OH, amide, alkoxy, aryloxy or heteroaryloxy.
Compounds of formula (IIA) have at least one chiral center and may exist in more than one diastereoisomeric form. The invention includes within its scope all enantiomers, and diastereosomers and the mixtures thereof.
The compounds of formula III have the following structure: 
wherein
n=1-3, where n=1 is preferred
R1 and R2 are independently xe2x95x90CH3; xe2x80x94(CH2)m, where m=4-8, m=4 is most preferred; xe2x80x94CH2CH(OH)(CH2)2xe2x80x94; CH2CH(F)(CH2)2xe2x80x94; xe2x80x94(CH2)2O(CH2)2xe2x80x94; or xe2x80x94(CH2)2CHxe2x95x90CHCH2xe2x80x94;
Ar=unsubstituted or mono- or di-substituted phenyl wherein said substituents are selected from the group consisting of halogen, OCH3, SO2CH3, CF3, amino, alkyl, and 3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;
X7 is
xe2x80x94NHSO2CH3; xe2x80x94NHP(O)(OBn)2; xe2x80x94NHP(O)(OH2; xe2x80x94(CH2)uNHSO2CH3; xe2x80x94(CH2)uNHC(S)NHCH(CO2H)(CH2)uCO2H; xe2x80x94CONHOH; or xe2x80x94(CH2)uCONHOH; wherein
u=1-5
or X7 is 
R6=xe2x80x94H or xe2x80x94Ac
R7=xe2x80x94NH(CH2)vCO2H; xe2x80x94NH(CH2)vCH(NH2)(CO2H); xe2x80x94NHCH(CO2H)(CH2)vNH2; xe2x80x94NH(CH2)vSO3H; xe2x80x94NH(CH2)vPO3H2; xe2x80x94NH(CH2)vNHC(NH)NH2; or xe2x80x94NHCH(CO2H)(CH2)vCO2H; and
X8=xe2x80x94CO2H; xe2x80x94NHSO2CH3; xe2x80x94NHP(O)(OBn)2; xe2x80x94NHP(O)(OH)2; xe2x80x94OP(O)(OBn)2; or xe2x80x94OP(O)(OH)2;
v=1-20.
The compounds of formula IIIA have the following structure: 
wherein
n=1-3, where n=1 is preferred;
R1 and R2 are independently xe2x95x90CH3; xe2x80x94(CH2)m, where m=4-8, m=4 is most preferred; xe2x80x94CH2CH(OR)(CH2)2xe2x80x94, wherein Rxe2x95x90H, alkyl, acyl or aroyl; CH2CH(F)(CH2)2xe2x80x94; xe2x80x94(CH2)2O(CH2)2xe2x80x94; or xe2x80x94(CH2)2CHxe2x95x90CHCH2;
Ar=mono- or di-substituted phenyl; wherein said substituents are selected from the group consisting of halogen, OCH3, OH, SO2CH3, CF3, NH2, alkyl, CN, unsubstituted and substituted sulfamoyl groups;
Ar may also be substituted with
xe2x80x94NH(CH2)uCO2Rxe2x80x2; xe2x80x94NH(CH2)u(CHxe2x95x90CH)u(CH2)CO2Rxe2x80x2; xe2x80x94NHCO(CH2)u(CHxe2x95x90CH)u(CH2)uCO2Rxe2x80x2; xe2x80x94NHP(O)(OBn)2; xe2x80x94NHP(O)(ORxe2x80x2)2; xe2x80x94(CH2)uNHSO2CH3; xe2x80x94(CH2)uNHC(S)NHCH(CO2Rxe2x80x2)(CH2)uCO2Rxe2x80x2; xe2x80x94CONHOH; or xe2x80x94(CH2)uCONHOH;
xe2x80x83wherein
u=0-5;
Rxe2x80x2=H or lower alkyl;
or Ar is 
R6=xe2x80x94H or xe2x80x94Ac
R7=xe2x80x94NH(CH2)vCO2H; xe2x80x94NH(CH2)vCH(NH2)(CO2H); xe2x80x94NHCH(CO2H)(CH2)vNH2; xe2x80x94NH(CH2)vSO3H; xe2x80x94NH(CH2)vPO3H2; xe2x80x94NH(CH2)vNHC(NH)NH2; or xe2x80x94NHCH(CO2H)(CH2)vCO2H; and
X8=xe2x80x94CO2H; xe2x80x94NHSO2CH3; xe2x80x94NHP(O)(OBn)2; xe2x80x94NHP(O)(OH)2; xe2x80x94OP(O)(OBn)2; or xe2x80x94OP(O)(OH)2;
v=1-20.
X7 is H; halogen; OH; OCH3; CF3; NO2; NH2; amino substituted with acyl, carbamate, alkyl or aryl sulfonates; CORxe2x80x2 where Rxe2x80x2 is OH, amide, alkoxy, aryloxy or heteroaryloxy.
Compounds of formula (IIIA) have at least one chiral center and may exist in more than one diastereoisomeric form. The invention includes within its scope all enantiomers, and diastereosomers and the mixtures thereof.
The compounds of formula IV have the following structure: 
wherein
n=1-3, where n=1 is preferred
R1 and R2 are independently xe2x95x90CH3; xe2x80x94(CH2)m, where m=4-8, m=4 is most preferred; xe2x80x94CH2CH(OH)(CH2)2xe2x80x94; CH2CH(F)(CH2)2xe2x80x94, xe2x80x94(CH2)2O(CH2)2xe2x80x94; or xe2x80x94(CH2)2CHxe2x95x90CHCH2xe2x80x94;
R3 and R4 are independently H; OCH3; alkyl; or Cxe2x80x94O(CH2)2;
X9=1-4 substituents selected from the groups consisting of
xe2x80x94halogen; xe2x80x94CF3; xe2x80x94OCH3; xe2x80x94SO2NH(CH2)qCO2H; xe2x80x94CONH(CH2)qCO2H; xe2x80x94NH2; xe2x80x94NHSO2CH3; xe2x80x94NHP(O)(OBn)2; xe2x80x94NHP(O)(OH)2; xe2x80x94SO2CH3; xe2x80x94OP(O)(OBn)2; xe2x80x94OP(O)(OH); xe2x80x94CO2H; xe2x80x94O(CH2)qCO2H; xe2x80x94O(CH2)qSO3H, xe2x80x94O(CH2)qOPO3H2; wherein
q=1-20.
or X9 is 
xe2x80x83wherein
t=1-20
R5=xe2x80x94H or xe2x80x94Ac
X6xe2x80x94CO2H; xe2x80x94NHSO2CH3; xe2x80x94NHP(O)(OBn)2; xe2x80x94NHP(O)(OH)2; xe2x80x94OP(O)(OBn)2; or xe2x80x94OP(O)(OH)2.
The compounds of formula IVA have the following structure: 
wherein
n=1 -3, where n=1 is preferred
R1 and R2 are independently xe2x95x90CH3; xe2x80x94(CH2)m, where m=4-8, m=4 is most preferred; xe2x80x94CH2CH(OR)(CH2)2xe2x80x94; wherein Rxe2x95x90H, alkyl, acyl, or aroyl; CH2CH(F)(CH2)2xe2x80x94; xe2x80x94(CH2)2O(CH2)2xe2x80x94; or xe2x80x94(CH2)2CHxe2x95x90CHCH2xe2x80x94;
R3 and R4 are independently H; OCH3; alkyl; or xe2x80x94O(CH2)2;
X9=1-4 substituents selected from the groups consisting of
xe2x80x94halogen; xe2x80x94CF3; OH, xe2x80x94OCH3; xe2x80x94SO2NH(CH2)qCH3; xe2x80x94NH(CH2)qCORxe2x80x2; xe2x80x94NH(CH2)q(CHxe2x95x90CH)q(CH2)qCO2Rxe2x80x2; xe2x80x94NH(CH)q(CHxe2x95x90CH)q(CH)qCO2R; xe2x80x94NHCO(CH2)q(CHxe2x95x90CH)q(CH2)qCO2R; and xe2x80x94NHCO(CH)q(CHxe2x95x90CH)q(CH)qCO2Rxe2x80x2
xe2x80x83wherein
q=0-20
Rxe2x80x2=OH, lower alkyl, aryl ester or aryl amide.
Compounds of formula (IVA) have at least one chiral center and may exist in more than one diastereoisomeric form. The invention includes within its scope all enantiomers, and diastereosomers and the mixtures thereof.
The meaning of the terms used in the specification and the claims, unless otherwise denoted, are as follows.
The term xe2x80x9calkylxe2x80x9d as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 12 carbons in the normal chain, most preferably lower alkyl groups. Exemplary unsubstituted groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents include one or more of the following groups: halo, alkoxy, arylalkyloxy (e.g., benzyloxy), alkylthio, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy, carboxyl (xe2x80x94COOH), amino, alkylamino, dialkylamino, formyl, alkylcarbonyloxy, alkylcarbonyl, heterocyclo, aryloxy or thiol (xe2x80x94SH). Preferred alkyl groups are unsubstituted alkyl, haloalkyl, arylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl, hydroxyalkyl and alkoxyalkyl groups.
The term xe2x80x9clower alkylxe2x80x9d as used herein denotes such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain.
The terms xe2x80x9carxe2x80x9d or xe2x80x9carylxe2x80x9d as used herein or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplary unsubstituted groups include phenyl, biphenyl and naphthyl. Exemplary substituents include one or more, preferably three or fewer, nitro groups, alkyl groups as described above, and/or one or more groups described above as alkyl substituents. Preferred aryl groups are unsubstituted aryl and hydroxyaryl.
The terms xe2x80x9cheterocycloxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d as used herein alone or as part of another group, denote optionally substituted fully saturated or unsaturated, aromatic or non-aromatic cyclic groups having at least one heteroatom in at least one ring, preferably monocyclic or bicyclic groups having 5 or 6 atoms in each ring. The heterocyclo group may, for example, have 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring. Each heterocyclo group may be bonded through any carbon or heteroatom off the ring system. Preferred groups include those of the following formula, which may be bonded through any atom of the ring system: 
wherein r is 0 or 1 and T is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Nxe2x80x94R8 or xe2x80x94CHxe2x80x94R8 where R8 is hydrogen, alkyl, aryl or arylalkyl. Exemplary heterocyclo groups include the following: thienyl, furyl, pyrrolyl, pyridyl, imidazolyl, pyrrolidinyl, piperidinyl, azepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, morpholinyl, piperazinyl, 4-alkylpiperazinyl, 4-alkylpiperidinyl, 3-alkpyrrolidinyl, oxazolyl, pyrazolyl, thiophenyl, pyridazinyl, thiazolyl, triazoyl, pyrimidinyl, 1,4-dioxanyl, benzoxadiazolyl, and benzofurazanyl. Exemplary substituents include one or more alkyl groups as described above and/or one or more groups described above as alkyl substituents.
The terms xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein alone or as part of another group, denote chlorine, bromine, fluorine and iodine.
The term xe2x80x9cacylxe2x80x9d, as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxyl group from the group xe2x80x94COOH of an organic carboxylic acid. Exemplary groups include alkylcarbonyl, arylcarbonyl, or carbocyclo- or heterocyclocarbonyl. The term xe2x80x9cacyloxyxe2x80x9d, as used herein alone or as part of another group denotes an acyl group as described above bonded through an oxygen linkage (xe2x80x94Oxe2x80x94).
Peripherally-acting xcexa agonists can be prepared by the attachment of polar groups to non-peptide xcexa opioid receptor selective agonists, such as the arylacetamides. In designing the peripherally-acting ligands, the introduction of the polar groups may result in either retention or enhancement of antinociceptive potency and selectivity and also may increase the polarity of the ligand sufficient to reduce or eliminate CNS penetration across the blood-brain barrier (BBB). Thus, the identity and the positioning of the polar group(s) are important.
Using the prototypic arylacetamide, U50,488, as an example, the arylacetamide pharmacophore can be divided into three regions: the aromatic region, the central region, and the amine region. All three regions represent potential positions for the attachment of polar groups. 
Compounds of formula (I) of the present invention are made as follows.
A series of novel compounds were made based on the class of arylacetamides reported by Glaxo (J. Med. Chem. 1993, 36, 2075). Specifcally, compound 1 can be deprotected to yield intermediate 2, which can be derivatized by the attachment of a variety of polar groups (Scheme 1). 
The 3xe2x80x2-substituted series can be prepared via Scheme 2. The reduction of the Schiff base intermediate formed during the cyclization to 6 is expected to be stereoselective due to the directing effect of the neighboring hydroxymethyl group. Both intermediates 11 and 12 can be derivatized to confer peripheral selectivity.
The 5xe2x80x2-substituted series can be prepared via Schemes 3 and 4. Starting from N-t-Boc-O-MEM-D-serine, the 5xe2x80x2-(S) series can be prepared, and starting from from N-t-Boc-O-MEM-L-serine allows the preparation of the 5xe2x80x2-(R) series. 
wherein Ar, R1, R2, and n are defined in formula I. 
wherein Ar, R1, R2, and n are as defined in formula I. 
wherein Ar, R1, R2, and n are as defined in formula I. 
wherein Ar, R1, R2, and n are as defined in formula I.
Using Schemes 1-4 the following example compounds are made.
Intermediate 3 can be treated with t-butyl bromoacetate and deprotected to produce {4-[1-(3,4-Dichlorophenyl)acetyl-2R-(1-pyrrolidinyl)-methyl]piperazinyl}acetic acid (26).
Intermediate 3 can be reacted with methane sulfonyl chloride to produce [1-(3,4-Dichlorophenyl)acetyl-4-methanesulfonyl-2R-(1-pyrrolidinyl)methyl]piperazine (27).
Intermediate 3 can be coupled to N-t-Boc-L-aspartic acid-b-benzyl ester and deprotected to produce [4-S-Aspartic acid-a-amido-1-(3,4-dichlorophenyl)acetyl-2R-(1-pyrrolidinyl)methyl]piperazine (28).
Intermediate 11 can be treated with t-butyl bromoacetate and deprotected to produce Methyl-[2R-(O-2-acetic acid)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-3R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (29).
Intermediate 11 can be coupled to to N-t-Boc-L-aspartic acid-b-benzyl ester and deprotected to produce Methyl-[2R-(O-S-aspartic acid-a-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-3R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (30).
Intermediate 12 can be treated with methanesulfonyl chloride to produce Methyl-[4-(3,4-dichlorophenyl)acetyl-2R-(N-methanesulfonamido)aminomethyl-3R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (31).
Intermediate 12 can be coupled to 2S-isothiocyanato-succinic acid-dibenzyl ester and deprotected to yield Methyl-{4-[3,4-dichlorophenyl]acetyl-3R-[1-pyrrolidinyl]methyl-2R-[N-(succinic acid-2S-thioureido)]aminomethyl}-1-piperazinecarboxylate (32).
Intermediate 21 can be treated with t-butyl bromoacetate and deprotected to produce Methyl-[2S-(O-2-acetic acid)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (33).
Intermediate 21 can be coupled to to N-t-Boc-L-aspartic acid-b-benzyl ester and deprotected to produce Methyl-[2S-(O-S-aspartic acid-a-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (34).
Intermediate 22 can be treated with methanesulfonyl chloride to produce Methyl-[4-(3,4-dichlorophenyl)acetyl-2S-(N-methanesulfonamido)aminomethyl-SR-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (35).
Intermediate 22 can be coupled to 2S-isothiocyanato-succinic acid-dibenzyl ester and deprotected to yield Methyl-{4-[3,4-dichlorophenyl]acetyl-5R-[1-pyrrolidinyl]methyl-2S-[N-(succinic acid-2S-thioureido)]aminomethyl}-1-piperazinecarboxylate (36).
The 2R isomers of 33-34 and 35-36 can be prepared from intermediates 24 and 25, respectively to produce Methyl-[2R-(O-2-acetic acid)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (37). Methyl-[2R-(O-S-aspartic acid-a-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (38). Methyl-[4-(3,4-dichlorophenyl)acetyl-2R-(N-methanesulfonamido)aminomethyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (39). Methyl-{4-[3,4-dichlorophenyl]acetyl-5R-[1-pyrrolidinyl]methyl-2R-[N-(succinic acid-2S-thioureido)]aminomethyl}-1-piperazinecarboxylate (40).
The corresponding structural formulas are shown hereunder. 
Compounds of formula II of the present invention are made by peripheralization by substitutions of the benzo portion of the tetrahydronaphthyl ring of DuPont series of compounds with polar groups. 
Starting material or precursors of the starting material are commercially available and thus allows regiospecific substitutions of the tetrahydronaphthyl ring (Scheme 5). While 5-hydroxytetralone, 6-hydroxytetralone, 7-hydroxytetralone, and 7-aminotetralone derivatives are readily available, 5-aminotetralone could be prepared from 5-hydroxytetralone (J. Org. Chem. 1972, 37, 3570).
The tetralone derivatives can be converted to dihydronaphthyl derivatives and subjected to chemistry similar to that employed in the preparation of U50,488 derivatives. The resulting compounds are racemic mixtures that can be derivatized to confer peripheral selectivity. If necessary, the final compounds or one of the intermediates can be resolved to test both enantiomers. 
wherein R1, R2, and n are as defined in formula I.
Following the procedure shown in Schemes 5-7, the following example compounds are prepared.
Intermediate (xc2x1)-64 can be treated with t-butyl bromoacetate and deprotected to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(O-2-acetic acid)-hydroxy-2-(1-pyrrolidinyl)naphthyl]acetamide (72).
Intermediate (xc2x1)-65 can be treated with t-butyl bromoacetate and deprotected to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(O-2-acetic acid)-hydroxy-2-(1-pyrrolidinyl)naphthyl]acetamide (73).
Intermediate (xc2x1)-66 can be treated with methanesulfonyl chloride to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(N-methanesulfonamido)-amino-2-(1-pyrrolidinyl)naphthyl]acetamide (74).
Intermediate (xc2x1)-67 can be treated with methanesulfonyl chloride to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(N-methanesulfonamido)-amino-2-(1-pyrrolidinyl)naphthyl]acetamide (75).
Intermediate (xc2x1)-68 can be treated with glycine benzyl ester and deprotected to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(N-2-acetic acid)-carboxamido-2-(1-pyrrolidinyl)naphthyl]acetamide (76).
Intermediate (xc2x1)-69 can be treated with glycine benzyl ester and deprotected to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(N-2-acetic acid)-sulfonamido-2-(1-pyrrolidinyl)naphthyl]acetamide (77).
Intermediate (xc2x1)-70 can be treated with glycine benzyl ester and deprotected to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N 1-[1,2,3,4-tetrahydro-7-(N-2-acetic acid)-carboxamido-2-(1-pyrrolidinyl)naphthyl]acetamide (78).
Intermediate (xc2x1)-71 can be treated with glycine benzyl ester and deprotected to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(N-2-acetic acid)-sulfonamido-2-(1-pyrrolidinyl)naphthyl]acetamide (79). 
The compounds of formula III of the present invention are prepared by substituting the central phenyl ring with polar groups. 
Compound 80 and analogues undergo a variety of diazonium-involving reactions for the attachment of polar groups (Scheme 7). 
Using the procedure shown in Scheme 7, the following compounds are made.
Intermediate 81 can be treated with dibenzyl phosphoryl chloride followed by deprotection to produce 2-(3,4-dichlorophenyl)-N-methyl-N-{1-3-(O-phosphoryl)hydroxyphenyl-2-(1-pyrrolidinyl)ethyl}acetamide (87).
Intermediate 85 can be coupled to methanesulfonyl chloride to produce 2-(3,4-dichlorophenyl)-N-methyl-N-{1-[3-(N-methanesulfonamido)aminomethyl]phenyl-2-(1-pyrrolidinyl)ethyl}acetamide (88).
Intermediate 85 can be coupled to 2S-isothiocyanato succinic acid and deprotected to produce 2-(3,4-dichlorophenyl)-N-methyl-N-{1-[3-(N-succinic acid-2S-thioureido)aminomethyl]phenyl-2-(1-pyrrolidinyl)ethyl}acetamide (89).
Intermediate 80 can be treated with dibenzyl phosphoryl chloride followed by deprotection to produce 2-(3,4-dichlorophenyl)-N-methyl-N-{1-3-(N-phosphoramido)aminophenyl-2-(1-pyrrolidinyl)ethyl}acetamide (90). 
The compounds of formula IV may be prepared by Scheme 8. 
wherein R1, R2, R3, and R4 are defined in formulas III and IV.
The diamino intermediate 91 (J. Med. Chem. 1990, 33, 286) can be coupled to different regioisomers of nitrophenylacetic acid, which are all commercially available. Reduction of the nitro group provides an amino group for the attachment of polar groups. Alternatively, the amino intermediates 95-97 readily undergo diazonium chemistry that converts the amino groups to carboxyl and sulfonyl chloride groups. This allows the polar groups to be attached via different linkers.
Following the procedure in Scheme 8, the following compounds are made.
Intermediate 96 can be treated with methanesulfonyl chloride to produce (xe2x88x92)-(5a,7a,8xcex2)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-[4,5]dec-8-yl]-3-(N-methanesulfonamido)aminophenylacetamide (104).
Intermediate 98 can be coupled to glycine benzyl ester and deprotected to yield (xe2x88x92)-(5a,7a,8xcex2)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-[4,5]dec-8-yl]-3-(N-2-acetic acid)sulfonamidophenylacetamide (105).
Intermediate 99 can be coupled to glycine benzyl ester and deprotected to yield (xe2x88x92)-(5a,7a,8xcex2)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-[4,5]dec-8-yl]-3-(N-2-acetic acid)carboxamidophenylacetamide (106). 
Compounds of the above formulas may have one or more asymmetric carbon atoms, Pure sterochemically isomeric forms of the above compounds may be obtained, and diastereoisomers isolated by physical separation methods, including, but not limited to crystallization and chromatographic methods. Cis and trans diasteriomeric racemates may be further resolved into their isomers. If separated, active isomers may be identified by their activity. Such purification is not, however, necessary for preparation of the compositions or practice of the methods herein.
As used herein, the compounds provided herein also include pharmaceutically acceptable salts, acids and esters thereof, stereoisomers, and also metabolites or prodrugs thereof that possess activity as analgesics but do not cause substantial CNS effects when administered or applied. Metabolites include any compound that is produced upon administration of the compound and metabolism thereof.
More detailed preparations of the compounds of the present invention follow.
Preparatory for the compounds of formula I, the following intermediates were prepared. 
N-Benzyl-D-serine(1)1: To a mixture of D-serine (25.0 g, 0.237 mol) and 200 mL anhydrous methanol was added sodium cyanoborohydride (11.95 g, 0.190 mol), while maintaining the temperature at 0xc2x0 C. with an ice bath. Then, benzaldehyde (26.5 mL, 0.261 mol) was added to the reaction flask, dropwise, at 30xc2x0 C. The mixture was stirred for 60 Hr. at room temperature. Then, the mixture was filtered and rinsed with methanol (50 mL). The white solid was dried in a vacuum oven at 40xc2x0 C. and 10 mmHg over 2 nights: 24.5 g. The filtrate was retained and the solvent was evaporated. This oil was passed through a silica gel column (10% MeOH/CH2Cl2) and 3.4 g of the desired compound was isolated. The total amount of the product was 27.9 g (60.0% yield). 1H NMR (DMSO-d6) xcex4 3.25 (m, 1H, CH), 3.85 (m, 2H, CH2), 4.11 (d, 2H, benzylic CH2), 7.45-7.53 (m, 5H, ArH).
Ref. 
(1) Ohfune, Y.; Kurokawa, N.; Higuichi, N.; Saito, M.; Hashimoto, M.; Tanaka, T. An efficient one-step reductive N-monoalkyation of xcex1-amino acids. Chemistry Letters. 1984, 441-444. 
N-Benzyl-D-serine methyl ester(2): Hydrogen chloride (gas) was bubbled into anhydrous methanol for 10 minutes. Then, the solution was allowed to cool to room temperature. Then, N-benzyl-D-serine (24.6 gm, 0.126 mol) was added to the reaction flask and refluxed over night under dry nitrogen. Then, the solvent was evaporated and dissolved in dichloromethane (200 mL), and washed with a saturated solution of sodium bicarbonate. The dichloromethane layer was dried with magnesium sulfate and the solvent was evaporated. (23 gm, 87.2% yield). 1H NMR (CDCl3) xcex4 3.41 (d, 1H, CH), 3.52-3.80 (dd, 2H, benzylic ), 3.69 (s, 3H, OMe), 7.27 (s, 5H, ArH).
N-[(1,1-Dimethylethoxy)carbonyl-D-Ser-(O-Bzl)-N-benzyl-D-Ser-OMe(3): To a solution of N-boc-D-serine-(O-bzl)OH (15 g, 50.76 mmol) in anhydryous dichloromethane (200 mL) was added HOBt (7.54 g, 55.8 mmol) at 0xc2x0 C. under dry nitrogen. Then, DCC (11.5 g, 55.7 mmol) in dichloromethane (100 mL) was added dropwise to the reaction flask. Then, this mixture was stirred for 1 Hr. Then, N-benzyl-D-serine-OMe (10 g, 47.8 mmol) in dichloromethane (100 mL) was added dropwise to the reaction flask. Then, stirred for 4 days. Then, filtered and rinsed with dichloromethane (100 ml). The white precipitate was DCU and HOBt. The filtrate was evaporated and re-dissolved in ethyl acetate (100 mL). Then, this was allowed to precipitate, overnightxe2x80x94more DCU. This was filtered and rinsed with ethyl acetate. Then, this was isolated on a silica gel column (20% ethyl acetate/hexanes): an oil-17.3 g, 74.3% yield. 1H NMR (CDCl3) xcex4 1.43 (s, 9H, t-Bu), 3.54 (t, 1H, OH), 3.72 (s, 3H, OMe), 3.75 (dd, 2H, CH2) 3.79 (dd, 2H, CH2), 4.41 (d, 2H, CH2 benzylic), 4.43 (d, 2H, CH2 benzylic), 7.27-7.30(m, 10H, ArH).
(2R,5R)-2-((Benzyloxy)methyl)-5-(hydroxymethyl)-4-(phenylmethyl)-3,6-piperazine dione(4)2: Into anhydrous chloroform (300 mL) was bubbled hydrogen chloride (gas). Then, the dipeptide (3) (13.5 g, 27.7 mmol) in chloroform (100 ml) was added to the reaction flask. The flask was stoppered and stirred for 64 Hr. Then, a saturated solution (100 ml) of sodium bicarbonate was added and stirred vigorously for 48 Hr. The cyclization was completed at this point. The organic layer was separated from the aqueous layer in a 1 L separatory funnel. The product was isolated from a silica gel column, eluting with dichloromethane-methanol-0.88 ammonia (96:2:2) to give (4) as an amorphous solid (6.0 g, 61.1% yield). 1H NMR (CDCl3) xcex4 3.72-3.96 (m, 7H), 3.97-5.24 (dd, 2H, CH2 benzylic), 4.45 (dd, 2H, CH2 benzylic), 715-7.30 (m, 10H, ArH); MS (FAB) m/e 355 (MH+).
Ref. 
(2) Williams, T. M.; Ciccarone, T. M.; MacTough, S. C. and et al. 2-Substituted piperazines as constrained amino acids. J. Med. Chem. 1996, 39, 1345-1348. 
(2S,5S)-2-((Benzyloxy)methyl)-4-(phenylmethyl)-5-piperazinemethanol(5): A suspension of lithium aluminum hydride (0.9 g, 23.7 mmol) in anhydrous tetrahydrofuran (40 mL) was treated with a solution of piperazinedione 4 (2.1 g, 5.92 mmol) in anhydrous tetrahydrofuran (200 mL). The reaction mixture was heated at reflux for 24 Hr and then, stirred at room temperature for 12 Hr. Water (10 ml) was added followed by aqueous sodium hydroxide (1N, 10 mL) and water (10 mL). The mixture was filtered, and the filtrate was evaporated to give 5 (1.67 g, 86.4% yield) as a viscous oil. 1H NMR (CDCl3) xcex4 2.58 (dd, 2H, CH2), 2.61 (t, 1H, OH), 3.10 (dd, 2H, CH2), 3.25 (dd, 2H, CH2), 3.50 (dd, 2H, CH2), 3.74 (s, 2H, CH2), 4.41 (dd, 2H, CH2 benzylic), 7.20-7.30 (m, 10H, ArH).
(2S,5S)-Methyl 2-[(Benzyloxy)methyl]-5-(hydroxymethyl)-4-(phenylmethyl)-1-piperazine carboxylate (6)3: A solution of 5 (1.67 g, 5.11 mmol.) in acetonitrile (20 mL) was treated with a solution of methyl chloroformate (0.532 g, 5.63 mmol) in acetonitrile (10 mL) at 0xc2x0 C. The mixture was stirred at ambient temperature for 30 min., and then aqueous sodium carbonate solution (15 mL) was added. The organic solvent was removed, and the aqueous residue was extracted with chloroform (3xc3x9710 mL). The combined organic extracts were washed with aqueous sodium carbonate solution (10 mL), dried, and evaporated to give 6 (1.52 g, 77.3% yield) as an oil. 1H NMR (CDCl3) xcex4 2.54 (dd, 2H, CH2), 2.45 (t, 1H, OH), 2.72 (dd, 2H, CH2), 3.51 (dd, 2H, CH2), 3.67 (dd, 2H, CH2), 3.69 (s, 3H, OMe), 3.81 (dd, 2H, CH2), 4.44 (dd, 2H, CH2 benzylic), 7.17-7.31 (10H, ArH).
(2S,5S)-Methyl 2-[(Benzyloxy)methyl]-5-[(1-pyrrolidinyl)methyl]-4-(phenylmethyl)-1-piperazinecarboxylate (7)3: A solution of oxalyl chloride (0.545 mL, 6.24 mmol) in dichloromethane (10 mL) at xe2x88x9265xc2x0 C. was treated with a solution of dimethyl sulfoxide (1.14 mL, 16.0 mmol) in dichloromethane (5 ml) maintaining the reaction temperature below xe2x88x9265xc2x0 C. The mixture was stirred at xe2x88x9270xc2x0 C. for 10 min, and then a solution of the piperazinemethanol (6: 2 g, 5.19 mmol) in dichloromethane (20 mL) was added at such a rate that the reaction temperature was maintained below xe2x88x9265xc2x0 C. The reaction mixture was stirred at xe2x88x9265xc2x0 C. for 3 Hr, and a solution of N-methylmorpholine (1.42 mL, 12.91 mmol) in dichloromethane (5 mL) was added. The mixture was stirred at xe2x88x9220xc2x0 C. for 45 min and then washed with ice-cold hydrochloric acid (0.01 N, 100 mL and 50 mL), dried, evaporated, and placed on a high vacuum pump overnight. The residue was dissolved in methanol (10 mL) and was added to a solution of pyrrolidine (0.91 mL, 10.94 mmol) in methanol (10 mL) at xe2x88x9210xc2x0 C., which had been adjusted to pH 6.0 by the addition of methanolic hydrogen chloride. Sodium cyanoborohydride (0.67 g, 10.66 mmol) and 4-xc3x85 molecular sieves (0.66 g) were added, and the mixture was stirred at ambient temperature for 18 Hr. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was dissolved in aqueous sodium carbonate (1M, 25 mL) and extracted with dichloromethane (2xc3x9750 mL). The product was isolated from a silica gel column, eluting with dichloromethane-methanol (98:2) to give (7: 1.0 g, 23.0% yield). 1H NMR (CDCl3) xcex4 1.75 (m, 4H, CH2CH2), 2.46 (m, 3H), 2.48 (m, 4H, CH2CH2), 2.55 (dd, 2H, CH2), 2.70-2.85 (m, 3H), 3.41 (dd, 2H, CH2), 3.69 (s, 3H, OMe), 4.10 (m, 1H), 4.20 (m, 1H), 4.41 (dd, 2H, CH2 benzylic), 7.10-7.31 (m, 10H, ArH); MS (FAB) m/e 438 (MH+).
(3) Naylor, A.; Judd, D. B.; Lloyd, J. E.; Scopes, D. I. C.; Hayes, A. G.; Birch, P. J. A potent new class of k-Receptor agonist: 4-subtituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines. J Med. Chem. 1993, 36, 2075-2083. 
(2S,5S)-Methyl 2-(hydroxymethyl)-5-[(1-pyrrolidinyl)methyl]-1-piperazine carboxylate(8): A solution of 7 (0.25 g, 0.571 mmol) in ethanol (200 mL) was hydrogenated over 10% palladium on carbon (Degussa type E101NE/W) at 50 psi for 7 days. Then, filtered through celite and filtrate was evaporated. (0.13 g, 0.5 mmol: 87% yield).
(2S,5S)-Methyl 4-[(3,4-dichlorophenyl)acetyl]-2-(hydroxy)methyl-5-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate(9): To a solution of 1,1xe2x80x2- carbonyldiimiazole (0.20 g, 1.26 mmol) in dichloromethane (10 mL) was added portionwise 3,4-dichlorophenylacetic acid (0.25 g, 1.26 mmol) and the resulting solution stirred under nitrogen for 1 Hr, at room temperature. A solution of 8 (0.13 g, 0.5 mmol) in dichloromethane (10 mL) was added and the mixture at room temperature for 18 Hr. The reaction mixture was washed with sodium carbonate solution (2 N, 2xc3x9710 mL), dried, and evaporated to give a viscous oil. This material was dissolved in a mixture of tetrahydrofuran (5 mL) and water (5 mL) and treated with lithium hydroxide (42 mg, 1.0 mmol). The reaction mixture was removed, and the aqueous residue was extracted with dichloromethane (3xc3x9710 mL). The combined organic extracts were dried and evaporated to give a colorless gum which was purified by flash column chromatography on silica gel, eluting with ethyl acetate-methanol (40:1) to give 9 (155 mg, 70%) as a colorless foam.